My colleagues and I want to know (1) how the nervous system makes decisions at the level of individual neurons and of neuronal circuits and (2) how the decision-making process is affected by life experiences. We ask these questions in an exquisitely approachable nervous system, that of the medicinal leech. Using voltage- sensitive dyes, we record activity in much of the animal's nervous system simultaneously as it decides whether to crawl, swim, feed, or bend. We also use photosensitive dyes that can activate or inactivate small groups of neurons to determine their contribution to decisions. We will first correlate activity in single neurons with particular choices, then activate or silence candidate decision-making neurons while they are make decisions. Having found neurons involved in these choices, we will now focus on three aspects of decision-making: 1. Do neuromodulators affect choice? These substances can modify the strengths of synapses, thus functionally rewiring a neuronal circuit. We will ask how the neuromodulators serotonin and dopamine affect decision-making. 2. Does the dynamical state of interactions among a set of neurons affect choice? One set of interconnected neurons could produce different stable activity states depending upon how the system is activated. 3. Does making a choice depend on increasing the gain in a particular behavioral circuit? Modifying gain might modify decision-making in a way that depends on mood or metabolic state: in the same circumstances, a hungry, excited animal will choose differently than a sated, relaxed one. Serotonin and dopamine have been strongly implicated in such changes in behavioral state, and we will determine how they modify the responsiveness of the decision-making neurons. Understanding the decision-making process is important; people who consistently make bad choices can end up in the hospital, in jail, or dead. The need for basic research about these processes is made clear from a recent quotations from the on-line textbook, Neuropsychopharmacology: The Fifth Generation of Progress: Serotonin...has been implicated in almost every conceivable physiologic or behavioral function-affect, aggression, appetite, cognition, emesis, endocrine function, gastrointestinal function, motor function, neurotropism, perception, sensory function, sex, sleep and vascular function. Moreover, most drugs that are currently used for the treatment of psychiatric disorders (e.g., depression, mania, schizophrenia, autism, obsessive-compulsive disorder, anxiety disorders) are thought to act, at least partially, through serotonergic mechanisms. (GK Aghajanian, AE Sanders-Bush Serotonin). Malfunctions in the dopamine system lead to horrors like addiction, psychosis, and Parkinson's Disease. Basic research using a powerful model system will allow us to sort out the many roles of serotonin and dopamine, and to determine how they affect decision-making. PUBLIC HEALTH RELEVANCE I propose to find out, at the level of individual neurons, how a brain operates: how it makes generates behaviors, how it makes decisions, and how those decisions are modified by the state of the animal. My laboratory uses a model system-the brain of a simple worm-because we can hope to answer these questions in rigorous ways. The comparative approach has a long and fruitful history: questions answered in simple animals provide information and inspiration for asking the same questions in more complex animals, like rats, monkeys, and eventually humans.